We recently showed that a new prophylactic vaccination regimen elicited immunity in Indian rhesus macaques that strongly suppressed SIVmac239 infection following mucosal challenge. The effective primeboost vaccination regimen is based on priming with electroporated rDNA encoding the complete SIVmac239 proteome and IL-12 followed by an rAd5 vector boost delivering the same SIV immunogens. Vaccinated animals were able to reduce SIVmac239 genome copies in the blood during chronic infection by a median value of 4 Log units demonstrating a magnitude of control that has been observed rarely before with experimental SIV vaccines. Our HIVRAD Team intends to use this finding to accomplish several important objectives that will advance HIV vaccine design including: 1) determine the nature of the potent immune responses evoked by vaccination and subsequent challenge with homologous SlVmac251 or heterologous SIVsmESSO; 2) determine the composition of vaccine immunogens needed to elicit protective immunity; and 3) advance the vaccination regimen towards a viable clinical candidate by developing Ad35 vectors and determining whether they effectively substitute for rAd5. Our Vector Core will provide the rDNA, rAd5, and rAd35 vectors needed to achieve the objectives of this HIVRAD application work plan.